Schizophrenia is a serious disease affecting one percent of the entire global population including about three million Americans. The annual cost of this disorder to the United Sates alone due to loss of employment, hospitalizations, medications, and the like exceeds 60 billion dollars annually and its toll in human suffering is shown by the ten to thirteen percent suicide rate for people who have the disease (American Psychiatric Association Public Information Online [1998] http://www.psych.org). A permanent or long-term cure for this tragic disease would be of tremendous value to the human race.
Schizophrenia appears to be genetically transmitted. Concordance rates of monozygous twins has been shown to be 48 percent while for dizygous twins concordance was only 17 percent. Concordance for offspring having two schizophrenic parents was 46 percent, while for those with only one schizophrenic parent, concordance was 17 percent. The "schizophrenic" environment and being raised by a schizophrenic parent or step-parent also increases the likelihood of this illness manifesting in exposed children. (Rosenhan, D., and Seligman, M. [1995], Abnormal Psychology, 3d. Ed., Norton & Co, NY, p. 443). Finding an effective treatment could also decrease the prognosis of schizophrenia in children being raised by someone who suffers from this illness.
The symptoms of schizophrenia can be grouped into three separate categories. These are (1) positive symptoms related to hallucinations and reality distortion; (2) disorganized symptoms characterized by attentional impairment and thought disorder; and (3) negative symptoms such as apathy and loss of verbal fluency (O'Donnell, P. O. and Grace, A. A. [1998], "Dysfunctions in multiple interrelated systems as the neurobiological bases of schizophrenic symptom clusters," Schizophrenia Bull., 24(2):267-283). A long history of research has demonstrated the efficacy of D2 receptor antagonism in the alleviation of positive and disorganized symptoms (Gray, J. A. [1998], "Integrating schizophrenia," Schizophrenia Bull., 24(2): 249-266). Persistence of negative symptoms often continues, even following neuroleptic treatment (Arndt, S. et al. [1995], "A longitudinal study of symptom dimensions in schizophrenia," Arch. Gen. Psychiatry, 52:352-359). The stability of negative symptoms has been, by some, attributed to the neuroleptic medications themselves (Carpenter, W. T. [1997], "The risk of medication-free research," Schizophrenia Bull., 23(1): 11-18).
Dysfunction of the limbic-cortical system may be implicated in all three types of symptoms. Reduced excitory glutamatergic inputs from the hippocampus and other limbic structures to the ventral striatum may be implicated in positive symptoms of psychosis and thought disorganization, and negative symptoms are likely to result from abnormal functioning of frontal lobe structures, e.g. those that receive connections from limbic structures, and/or anatomical irregularities. (Csernansky, J. G. and Bardgett, M. E. [1998], "Limbic-Cortical Neuronal Damage and the Pathophysiology of Schizophrenia," Schizophrenia Bull. 24(2):231-248.)
Excess dopamine production is implicated in schizophrenia. The dopamine hypothesis of schizophrenia associates the disease with increased activity in dopaminergic neurons. Schizophrenic symptoms may be caused by an abnormal dopaminergic state brought about by a primary limbic-cortical lesion and deficits in glutamatergic inputs to the ventral striatum. (Csernansky, J. G. and Bardgett, M. E. [1998], supra.) Radiotracer studies have shown elevated D2 dopamine receptor levels in schizophrenic patients with increases in striatal dopamine receptors sometimes many times increased over normal values. (Seeman, P. et al. [1993], "Dopamine D2 receptors elevated in schizophrenia," Nature, 365:441-445; Tune, L. E. et al. [1993], "Dopamine D2 Receptor Density Estimates in Schizophrenia: A Positron Emission Tomography Study with .sup.11 C-N-Methylspiperone," Psychiatry Research 49:219-237.) Pharmacologically-invoked dopamine release is estimated to be 300% higher than normal levels. (Breier, A. et al. [1997], "Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentration: evidence from a novel positron emission tomography method," Proc. Nat'l Acad. Sci., 94(6):2569-2574.) Dopamine projections from the substantia nigra modulate striatal neuronal activity via dopamine D1 and D2 receptors. (Egan et al. [1997], "Treatment of Tardive Dyskinesia," Schizophrenia Bull. 23(4):583-609).
One of the strongest pieces of evidence for a dopamine disturbance in schizophrenia arises from the ability of D2 receptor antagonists to alleviate schizophrenic symptoms.
Effective antipsychotics acting on D2 receptors, including "typical" antipsychotics such as haloperidol and "atypical" antipsychotics such as clozapine, result in disruptions of the dopamine system. Long-term haloperidol treatment reduces the activity of dopamine cells in the substantia nigra. Clozapine reduces the activity of dopamine cells in mesolimbic/mesocortical cells in the ventral tegmental area that projects to the limbic system. (O'Donnell, P. and Grace, A. A. [1998], "Dysfunctions in Multiple Interrelated Systems as the Neurobiological Bases of Schizophrenic Symptom Clusters," Schizophrenia Bull. 24(2):267-284.)
Past research has demonstrated a prominent role for dopamine and D2 receptors in the manifestation of psychosis, progression and complications of this disorder. More recent research has uncovered a multitude of abnormalities of the dopamine system itself and in its relation to other neurotransmitter systems in schizophrenia. A review of these studies will convey a general understanding of other more subtle symptoms involved in schizophrenia which manifest from excessive stimulation of other than D2 dopamine receptors.
The five distinct dopamine receptors have been clustered into two families: the D1-like dopamine receptors consist of the D1 and D5 receptors; and the D2-like dopamine receptors consist of the D2, D3 and D4 receptors, the latter having high affinities for a number of antipsychotic drugs. (Damask, S. P. et al. [1996], "Differential effects of clozapine and haloperidol on dopamine receptor mRNA expression in rat striatum and cortex," Molecular Brain Res. 41:241-249.) D4 receptors have been found to be elevated in schizophrenia. (Seeman, P. et al. [1993], "Dopamine D4 receptors elevated in schizophrenia," Nature 365:441-445.) The "typical" antipsychotics that are highly effective in reducing hallucinations and delusions are selective antagonists of D2 receptors. The "atypical" antipsychotics, to which negative symptoms such as affective flattening, and lack of motivation respond, show affinity for both D1 and D2 receptors. (Swerdlow, Neal R. and Geyer, Mark A., "Using an Animal Model of Deficient Sensorimotor Gating to Study the Pathophysiology and New Treatments of Schizophrenia," Schizophrenia Bulletin 24(2):285-301; Benes, F. M., "Model Generation and Testing to Probe Neural Circuitry in the Cingulate Cortex of Postmortem Schizophrenic Brain," Schizophrenia Bull. 24(2):219-230.) The D.sub.1 receptor is broadly distributed, while the D.sub.5 receptor is restricted to expression in the hippocampus, thalamus and hypothalamus in the rodent. D.sub.2, D.sub.3 and D.sub.4 have high affinities for dopaminergic antagonist drugs. The D.sub.2 receptor appears to be expressed in most dopaminoceptive regions of the brain including motor and limbic structures. The D.sub.3 and D.sub.4 receptors are enriched in subcortical limbic system components. (Damask, S. P. et al., "Differential expression in rat striatum and cortex," [1996] Molecular Brain Res. 41:241-249.)
More recent studies have demonstrated the involvement of D1, D3 and D4 receptors as contributing to other symptoms of schizophrenia. For example, D1 receptor antagonism correlates highly (r-0.97) with attenuated response in conditioned avoidance tasks that is a predeterminant of neuroleptic efficacy (McQuade, R. D. et al. [1992], "In vivo binding to dopamine receptors: a correlate of potential antipsychotic activity," Eur. J Pharmacol. 215(1):29-34). Also, researchers have demonstrated that D1 receptors located in the caudal portion of the striatum, when agonized, activate one of the strongest functional projections related to the auditory cortex (Arnauld, E. et al. [1996], "Involvement of the caudal striatum in auditory processing: c-fos response to cortical application of picrotoxin and to auditory stimulation," Molecular Brain Res. 41:27-35). This may be a contributory source of auditory hallucinations. This sensory-neural pathway has not been fully researched. D3 receptor targeting medications are being evaluated for both their antipsychotic properties (antagonism) and Parkinsonian symptom alleviating (agonism) effects (Sokoloff, P. et al. [1990], "Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics," Nature 347:146-151). Finally, D4 receptor antagonism has been demonstrated to restore prepulse inhibition (PPI), a sensory gating mechanism that is deficient in schizophrenia (Swerdlow, N. R. and Geyer, M. A. [1998], "Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia," Schizophrenia Bull., 24(2):285-301). Most medications fail to address all the symptoms that can be alleviated by reducing dopamine availability to all these mid-brain receptor subtypes. Dopamine antagonizing medications such as clozapine in psychosis-controlling doses occupy at least 70% of these receptors, as was demonstrated in a recent radioligand study (Seeman, P. and Kapur, S. [1997], "Clozapine occupies high levels of dopamine D2 receptors," Life Sciences 60(12):207-216). To a certain degree, antagonism of all dopamine receptors (except D5 which is much more limited in expression) contributes to restorative effects in function.
Studies of psychotomimetic drugs also indicate a relationship between dopaminergic transmission and the positive symptoms of schizophrenia. For example, amphetamine, an indirect dopamine agonist, has psychotomimetic effects. Gray, J. A. (1998), "Integrating Schizophrenia," Schizophrenia Bull. 24(2):249-265. A study of amphetamine-induced dopamine striatal 11c-raclopride binding reduction levels confirmed that patients with schizophrenia had significantly higher binding reductions (-22.3%.+-.2.7 vs.-15.5%.+-.1.8). (Breier, A. et al. [1997], "Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method," Proc. Nat'l. Acad. Sci. USA 94(6):2569-2574).
N-methyl-d-aspartate (NMDA) antagonists such as phenylcyclidine (PCP), also known as "angel dust," and ketamine, induce symptoms resembling schizophrenia. The effective antipsychotic, clozapine, preferentially increases glutamate levels in the prefrontal cortex and reverses behavioral effects of these antagonists, giving rise to the hypothesis that NMDA disturbances are indicated in schizophrenia. Enhanced dopamine may be involved in the effects seen after administration of these NMDA antagonists. Tests show significantly decreased 11c-raclopride binding to dopamine receptors in the striatum after administration of ketamine. (Breier, A. et al. [1998], supra).
There are four main dopaminergic pathways in the mammalian brain: (1) The mesocortical pathway runs from the ventral tegmental part of the mesencephalon to the frontal cortex, and is implicated in schizophrenia. (2) The mesolimbic pathway runs from the mesencephalon to the limbic areas such as the amygdala, hippocampus and nucleus accumbens (Nac) and is also implicated in schizophrenia. Along with the mesocortical pathway, the mesolimbic pathway arises in the ventral tegmental area (VTA) of the mesencephalon. (3) The nigral striatal pathway projects from its cell bodies in the substantia nigra (SN) to the striatum (ST) and is also implicated in schizophrenia (as well as being the one lesioned for the "Parkinson's model in lab animals). The nigral striatal pathway has excessive D.sub.2 /D.sub.3 receptor sites. (4) The tuberinfundibular tract runs from the hypothalamus to the anterior pituitary and has not been implicated in schizophrenia. It mediates the release of prolactin. (Pies, R. [1997], "What differentiates prototypical atypical antipsychotics?" http://www.mhsource.com.)
Reducing dopamine availability in the mesolimbic and striatal regions via depolarization block (Chiodo et al. [1983], "Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons," J. Neuroscience 3:1607-1619) and receptor antagonism is not inherently compensated for by mesencephalic dopamine receptor upregulations. In a study done by S. P. Damask et al. ([1996], Differential effects of clozapine and haloperidol on dopamine receptor mRNA expression in the rat striatum and cortex," Molecular Brain Res. 41:241-249), the up and down regulation of mRNA expression for dopamine receptors was mapped in response to haloperidol and clozapine. This study indicates no evidence of compensatory upregulation of mRNA activity in the basal ganglion. Several areas of the basal ganglia were demonstrated to have a reduction of mRNA activity in response to blockage of receptors and neural firing. Significant increases of dopamine receptor mRNA expression were observed in the cerebral cortex and temporal lobes. This may eventually contribute to the homeostasis of the cortical/subcortical circuitry. It seems there is an inverse reciprocal link between dopamine transmission in the frontal cortex and subcortical areas, especially the nucleus accumbens (Gray, J. A. [1998], "Integrating schizophrenia, "Schizophrenia Bull." 24(2):249-266), which has both striatal and limbic components.
Medication non-compliance is present in all forms of illness. It presents one of the most vexing challenges in psychopharmacology (Fenton, W. S. et al. [1997], "Determinants of medication compliance in schizophrenia: empirical and clinical findings," Schizophrenia Bull. 23(4):637-65 1). "Non-compliance is seen to create particular medical and social problems when the drugs concerned are neuroleptics (anti-psychotics) such as chlorpromazine or haloperidol" (Rogers, A. et al. [1998], "The meaning and management of neuroleptic medication: A study of patients with a diagnosis of schizophrenia," Social Science and Medicine 47(9):1313-1323). There are numerous reasons patients with schizophrenia choose not to comply with a prescribed medication ritual. Between one-quarter and two-thirds of patients cite side effects as their primary reason for medication discontinuance (del Campo, E. J. et al. [1983], "Rehospitalized schizophrenics: what they report about illness, treatment and compliance," J. of Psychosocial Nurs. and Mental Health Serv. 21(6):29-33). Other studies have directly linked the severity of psychopathology with non-compliance in both inpatient and outpatient settings (Fenton, W. S. et al. [1997], "Determinants of medication compliance in schizophrenia: empirical and clinical findings," Schizophrenia Bull. 23(4):637-651). In a conglomeration of 26 studies using a variety of definitions and detection methods to assess medication use among outpatients, a default rate of 45% was reported (range -10% to 76%) of patients with schizophrenia taking oral medication (Young, J. L. et al. [1986], "Medication noncompliance in schizophrenia: codification and update," Bull. Am. Acad. of Psychiatry and the Law 14:105-122). Other studies have shown even higher incidences of non-compliance (up to 55%). In England, where adherence rates for neuroleptics converge at a 50% level, researchers concluded, "This rate of non-consumption of prescribed medications suggests that, for many individuals, non-compliance holds more benefits than compliance" (Rogers et al. [1998], supra, p. 1315). In and outside of the United States the numbers of chronic non-compliant patients remains exceedingly high. Patients who willingly discontinue medications often do not experience full "relapse" until weeks or months following discontinuance, thus they tend not to attribute the relapse to the medication discontinuance (Hertz, M. I. and Melville, C. [1980], "Relapseinschizophrenia," Am. J. Psychiatry 137(7):801-805). Non-compliance creates a "revolving door" pattern of relapse and re-hospitalization. This is problematic in that re-hospitalizations are a huge portion of the annual expenditure to treat schizophrenia. Furthermore, inability to achieve long-term symptom stabilization prevents the successful implementation of further rehabilitative measures, described in "The Patient Outcomes Research Teams" (Lehman. A. F. and Steinwachs, D. M. [1998], "Patterns of usual care for schizophrenia: Initial results from the schizophrenia patient outcomes research team (PORT) client survey," Schizophrenia Bull. 24(1):11-20).
Conventional treatments for schizophrenia using neuroleptic dopamine receptor antagonists give rise to many side effects, some more severe than the illness itself. (Rogers, A. et al. [1998], "The Meaning and Management of Neuroleptic Medication: A Study of Patients with a Diagnosis of Schizophrenia," Soc. Sci. Med. 47(9):1313-1323). The term "neuroleptic" means to "grip" or take control of the neurons, as is evident by the extrapyramidal side effects (EPS) of these drugs, such as seizures, acute dystonia, drug-induced Parkinsonism, akisthisia (inner restlessness and characteristic fidgety movements), tardive dyskinesia (involuntary movements such as chewing, lateral jaw movements, lip smacking and puckering), vermicular writhing and protrusions of the tongue, grimacing, forehead wrinkling, eye blinking and excessive winking and movements of the extremities, and irregular breathing and swallowing, and neuroleptic malignant syndrome (including seizures, dystonia and rigidity, fever, autonomic instability, delirium, myoglobinuria). Additional side effects include sexual dysfunction, urinary problems, hepatic dysfunction, ocular and dermatological problems, and cardiac and respiratory effects. As an example, the neuroleptic haloperidol is quite toxic and gives rise to motor disorders and tardive diskinesias after prolonged periods of administration. (Tarsy, D., and Baldessarini, R. J., In: Shah, N. and Donald, A., eds. Movement Disorders, New York: Plenum Press, [1986] pp. 240-243.) Dopamine blocking by the neuroleptic medications results in an excess of prolactin, causing such side effects as decreased sexual interest, anorgasmia, amenhorrhea and the like. (Hansen, T. et al. [1977], "Neuroleptic intolerance," Schizophrenia Bull. 23(4):567-582.) These side effects have led to the classification of some patients as neuroleptic-intolerant and treatment-resistant schizophrenic patients. (Conley, R. and Buchanan, R. [1997] "Evaluation of Treatment-resistant schizophrenia," Schizophrenia Bull. 23(4): 663-674. Such patients have often lost higher cortical functioning to the extent that they are unable to have a sense of spirituality in their lives or pray. Even in patients who are not neuroleptic-intolerant, these severe side effects are a major reason for patient noncompliance with neuroleptic medications (Fenton, W. S. et al. [1997], "Determinants of Medication Compliance in Schizophrenia: Empirical and Clinical Findings," Schizophrenia Bull. 23(4):637-651.)
Treatment resistance poses an additional challenge in the lives of people with schizophrenia and health care providers. In a state hospital study, the criteria for resistance were: failure to respond to two six-week drug trials (1,000 mg per day chlorpromazine equivalents), inpatient status of at least four months and at least four months hospitalization required in the preceding five years. It was discovered that 48% (n=803) of Connecticut State Hospital inpatients with a diagnosis of schizophrenia or schizo-affective disorder were treatment resistant (Essock, S. M. et al. [1996], "Clozapine eligibility among state hospital patients," Schizophrenia Bull. 722(1):15-25). Other studies have shown that the prevalence of treatment resistance ranges from one-third to one fifth of all patients diagnosed with schizophrenia (Conley, R. R. et al. [1997], "Evaluation of treatment-resistant schizophrenia," Schizophrenia Bull. 23(4):663-674). The cost of treatment for this disorder, as previously noted, is extremely high. The cost to care for individuals with treatment resistant forms of this illness is a disproportionately high percentage of the total cost (Revicki, D. A. et al. [1990], "Economic grand rounds: cost effectiveness of clozapine for treatment-resistant schizophrenic patients" Hospital and Community Psychiatry 41(8):850-854). This is due to patients being highly symptomatic and often requiring extensive periods of hospital care (McGlashan, T. H. [1990], "A selective review of recent North American long-term follow-up studies on schizophrenia," Schizophrenia Bull. 16(4):515-565).
Other therapies used for treatment of positive symptoms of schizophrenia include anti-Parkinson's drugs, anti-depressants, anti-anxiety drugs, and other adjunctive psychosis medications. Compliance by both patients and health care professionals to neuroleptic and other recommended treatment programs is extremely low. (Lehman, A. F. et al. [1998], "Patterns of Usual Care for Schizophrenia: Initial Results from the Schizophrenia Patient Outcomes Research Team (PORT) Client Survey," Schizophrenia Bull. 24:(1):11-20.) Physical side effects of medications may leave patients so debilitated that therapy must be provided to teach them to dress themselves, cook and function normally. Methods for adjusting patient dopamine levels are needed which do not lead to the serious side effects of the neuroleptic drugs.
Patients being treated with drugs for schizophrenia are often depressed due to feelings of helplessness and lack of control since they view their circumstances as internally caused, affecting every aspect of their lives, and permanent. Patients receiving medications to reduce dopamine levels are still subject to normal mood swings caused by fluctuations in dopamine levels, and providing a method for such patients to self-regulate their dopamine levels would be desirable in ameliorating depression by giving them feelings of greater control, and a sense that the nature of their condition is specific and temporary rather than global, embracing every aspect of their lives, and permanent.
Tardive Dyskinesia (TD) continues to be a significant clinical problem for both patients and doctors. New atypical neuroleptics were expected to eliminate the development of TD, but currently the condition remains prevalent among patients with long term neuroleptic use. Cumulative five year prevalence rates are 20-26%, ten year prevalence rates are 49%, and 25 year rates are 68%. Dopamine depleters, D1 antagonists, and D2 ligands, which have an antidopaminergic effect in the striatum, are a few methods of treating this neuroleptic induced disorder (Egan, M. F. et al. [1997], "Treatment of tardive dyskinesia," Schizophrenia Bull. 23(4):583-609). A study of neural physiological changes in neuroleptic induced TD primates revealed a significant reduction of regional 2-deoxyglucose uptake in the medial segment of the globus pallidus and in the ventral anterior and ventral lateral nuclei of the thalamus in the dyskinetic animals relative to neuroleptic nondyskinetic and controls (Mitchell, I. J. et al. [1992], "Regional changes in 2-deoxyglucose uptake associated with neuroleptic-induced tardive dyskinesia in the Cebus monkey," Movement Disorders 7(1):32-37). Some years prior to that discovery, several of the same researchers evaluated MPTP-induced regional 2-deoxyglucose uptake changes. They found there was a dramatic increase of 2-deoxyglucose in the globus pallidus and increased uptake in the ventral lateral nucleus of the thalamus (Mitchell, I. J. et al. [1986], "Neural mechanisms mediating 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in the monkey: relative contributions of the striatopallidal and striatonigral pathways as suggested by 2-deoxyglucose uptake," Neuroscience Letters 63:61-65). Findings from these studies indicate that MPTP causes an increase in 2-deoxyglucose uptake in the same areas that TD causes a decrease in 2-deoxyglucose uptake.
Hypofunctionality of the frontal and temporal lobes has been observed in numerous PET studies of the schizophrenic brain (Kawasaki, Y. et al. [1992], "Regional cerebral blood flow in patients with schizophrenia: A preliminary report," Eur. Archives of Psychiatry and Clinical Neuroscience, 241:195-200; Yurgelun-Todd, D. A. et al. [1996], "Functional magnetic resonance imaging of schizophrenic patients and comparison subjects during word production," Am. J. Psychiatry 153:200-205). It is believed that this may be contributory to negative symptoms. Damask et al. reported chronic neuroleptic (clozapine and haloperidol) administration invoked large upregulations of dopamine receptor transcripts in both the frontal and temporal lobes (Damask, S. P. et al. [1996], "Differential effects of clozapine and haloperidol on dopamine receptor mRNA expression in the rat striatum and cortex," Molecular Brain Res. 41:241-249).
Studies have demonstrated that the prefrontal cortex regulates the basal release of dopamine in the limbic system, an effect known to be mediated by the ventral tegmental area (VTA) (Karreman, M. and Moghaddam, B. [1996], The prefrontal cortex regulates the basal release of dopamine in the limbic striatum: an effect mediated by ventral tegmental area," J. Neurochemistry 66:589-598). Infusion of monoamines, such as dopamine, in the prefrontal cortex has an inhibitory effect on the pyramidal neurons that project to subcortical structures, inhibiting dopamine release in these areas (Sesack, S. R. and Bunney, B. S. [1989], "Pharmacological characterization of the receptor mediating electrophysiological responses to dopamine in the rat medial prefrontal cortex: a microiontophoretic study," J. Pharmacol. Exp. Ther. 248:1323-1333). This implies that dopamine release in the subcortical structures is attenuated by increased dopamine availability in the prefrontal cortex. Limbic-cortical and frontal-cortical functional abnormalities have been traced to these structural areas and pathways, resulting in disruption of this neural circuitry (Csernansky, J. G. and Bardgett, M. E. [1998], Limbic-cortical neuronal damage and the pathophysiology of schizophrenia," Schizophrenia Bull. 24(2):231-248). Furthermore, blockading the prefrontal cortex (PFC) dopamine receptors with neuroleptic medications in effect prevents the PFC from naturally down-regulating the release of dopamine in the VTA and subsequently into the limbic system.
A similar type of neural metabolic restoration of homeostasis has been observed with hypofrontality caused by Parkinson's Disease. When over-excited midbrain neurons are stereotaxically lesioned by the procedure of postero-ventral pallidotomy (PVP), there is a PET scan observable restoration of frontal cortex activity (East, R. [1996], "Victory over Parkinson's," http://xfdm08.aps1.anl.gov/PARKINSON/parkinson_victory.html# What_is_it).
In 1982, MPTP was introduced on the streets of California as a contaminant of a "synthetic heroin." A number of those who took the synthetic heroin in large amounts (4.5 grams in one reported case, 30 grams in a second, 16 ounces in a third, and one teaspoon per day for about a month in a fourth reported case) developed symptoms of severe Parkinson's Disease, but with no change in mental status. Neurotoxic effects appeared limited to damage to the substantia nigra. One individual who had taken low doses of MPTP showed significant destruction of nigrostriatal dopamine neurons; however, this patient had no symptoms of motor deficit or Parkinson's disease. A longitudinal follow-up of these individuals reported they are basically doing well and leading normal lives, albeit requiring daily Parkinsonian medications. There was no evidence of any cognitive deficits or peripheral damage (short- or long-term) due to large systemic exposure of MPTP other than a reported "burning sensation" during and shortly after the injection. (Ballard, P. A. et al. [1985], "Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): Seven cases," Neurology 35:949-956.)
MPTP has been used as a model to simulate Parkinson's disease in animal models because it selectively destroys the small group of dopaminergic nerve cells in the substantia nigra of the brain which are also destroyed by degenerative processes in naturally-occurring Parkinson's disease. (See, e.g. U.S. Pat. No. 5,599,991.)
MPTP is relatively harmless until converted into its active metabolite MPP+ by monoamine oxidase B (MOA-B). MPTP, as well as being a substrate for MOA-B, is also a mechanism-based inhibitor of this enzyme. (Krueger, M. J. et al. [1990], "Mechanism-based inactivation of monoamine oxidases A and B by tetrahydropyridines and dihydropyridines," Biochem. J. 268:219-224.) On exposure to MOA-B it is irreversibly converted into MPP+ and a small amount of MTDP+ is usually also formed (with a lesser degree of toxicity). After an intracranial injection of MPTP, one hundred percent recovery of this substance can be reobtained in its original and metabolite forms. (DiMonte, D. A. et al. [1996], "Astrocytes as the Site for Bioactivation of Neurotoxins," NeuroToxicology 17(3-4):697-704.)
Tipton, K. F. and Singer, T. P. (1993), "Advances in our Understanding of the Mechanisms of the Neurotoxicity of MPTP and Related Compounds," J. Neurochem. 61(4):1191-1206 is a review article discussing the biochemical actions of MPTP and its selective destruction of nigrostriatal dopaminergic neurons. MPP+ provides its toxic effects by penetrating the mitochondrial matrix where respiratory inhibitor rotenone and piericidin A react. This results in the augmentation of reducing agents from NADH dehydrogenase to reach ubiquinone [coenzyme Q (CoQ)], thus halting the process of oxidative phosphorylation. The necessity for MPP+ to accumulate in sufficiently high concentrations for this chain of events to occur means that most cell types are susceptible only to a transient decrease in ATP production. MPP+ is a substrate for the dopamine transporter mechanism and its high binding affinity to the neuromelanin present in the nigral dopamine neurons renders these neurons most susceptible to MPP+ toxicity.
MPTP is also a substrate and mechanism-based inhibitor of MAO-B (Krueger, M. J. et al. [1990], "Mechanism-based inactivation of monoamine oxidases A and B by tetrahydropyridines and dihydropyridines," Biochemistry J. 268:219-224). On exposure to MAO-B, MPTP is irreversibly converted into MPP.sup.+ and a small amount of MTDP.sup.+ is usually also formed (with a lesser degree of toxicity). After an intracranial injection of MPTP, 100% recovery of this substance can be obtained in is original and metabolite forms (Di Monte, D. A. et al. [1996], "Astrocytes as the site for bioactivation of neurotoxins," Neurotoxicology 17:697-704). This is a reliable indicator that no other unwanted reactions are occurring.
In studies evaluating the changes in brain energy production and enzyme levels with the administration of MPTP and neuroleptic medications, fascinating similarities in these compounds emerged. MPTP bears structural and pharmacological similarities to haloperidol, which is 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butano ne. Both undergo oxidation, resulting in neurotoxic metabolites MPP.sup.+ and HPP.sup.+ respectively (Rollema, H. et al. [1994], "MPP.sup.+ -like neurotoxicity of a pyridinium metabolite derived from haloperidol: In vivo microdialysis and in vitro mitochondrial studies," J. Pharmacology & Exp. Therapeutics 268:380-387). MPTP when administered in subtoxic doses was found to cause generalized reduction in NADH, ubiquinone oxidoreductase (complex I) in rat brain, as is seen with both haloperidol and fluphenazine. MPTP was further evaluated alongside the chronic administration of haloperidol, fluphenazine, and clozapine. All potentiate a moderate but generalized increase in monoamine oxidase-A and -B (MAO-A and -B) in the striatum and hippocampus. There existed a strong positive correlation between the hippocampal increase of MAO-A activity and an increase in COX (cytochrome-c oxidase, complex IV) activity, observed in the MPTP, clozapine, and fluphenazine groups. Based upon these results, observable reductions in COX activity in the schizophrenic brain are not the result of neuroleptic treatment, but rather COX is increased as a result of neuroleptic (and ironically MPTP) treatment, particularly in the glutamatergic rich regions of the hippocampus and frontal cortex. It is assumed this may contribute to the therapeutic value of these compounds (Prince, J. A. et al. [1997], "Neuroleptic-induced mitochondrial enzyme alterations in the rat brain," J Pharmacology and Exp. Therapeutics, 280:261-267).
MPP+ is also a neurotoxin to norepinephrine- and serotonin-containing neurons. (Namura, I. et al. [1987], "MPP+ (1-methyl-4-phenylpyridine) is a neurotoxin to dopamine-norepinephrine- and serotonin-containing neurons," Eur. J. Pharmacology 136:31-37).
Symptoms of Parkinson's are not usually detected until about eighty percent of the dopamine-producing neurons have died. (Harvard Parkinson's Web Page [1998] http://neuro-chief-e-mgh.harvard.edu/parkinsonsweb/Main/Drugs/agonist2. html.) In primate models, it has been shown that dosages of MPTP in the range of 0.66 mg/kg or more are necessary before symptoms of motor dysfunction occur, that higher dosages over a longer period are necessary for severe nerve cell loss, and that considerable reduction of dopamine may occur without the development of clinical evidence of disordered motor function. (Bums, R. S. et al. [1983], "A primate model of parkinsonism: Selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine," Proc. Nat'l. Acad. Sci. 80:4546-4550.) For antipsychotic effects of neuroleptics to occur, it has generally been found necessary to induce about 70-89% D.sub.2 receptor blockade. (Nyberg, S. et al. [1997], "A PET Study of 5-HT.sub.2 and D.sub.2 Dopamine Receptor Occupancy Induced by Olanzapine in Healthy Subjects," Neuropsychopharmacology 16(1):1-7.) However, neuroleptic dosages cause dopamine level reductions in much lesser amounts. (Patterson, T. A., and Schenk, J. O. [1991], "Effects of Acute and Chronic Systemic Administration of Some Typical Antipsychotic Drugs on Turnover of Dopamine and Potassium Ion-Induced Release of Dopamine in the Striatum of the Rat In Vivo," Neuropharmacology 30(9):943-952.)
MPP+ is accumulated in the dopamine neuronal uptake system and concentrated within dopamine neurons, accounting for their selective destruction. Some destruction of cells involved in norepinephrine and serotonin also occurs. (Javitch, J. A. et al. [1985], "Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: Uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity," Proc. Natl. Acad. Sci. 82:2172-2177.) The mesolimbic dopaminergic pathway is about twice as resistant as the nigrostriatal dopaminergic pathway to MPTP toxicity. (Hung, H.-C. and Lee, E. H. Y. [1996], "The mesolimbic dopaminergic pathway is more resistant than the nigrostriatal dopaminergic pathway to MPTP and MPP- toxicity: role of BDNF gene expression," Molecular Brain Res. 41:16-26; German, D. C. et al. [1988], "1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonian Syndrome in Macaca Fascilularis: Which Midbrain Dopaminergic Neurons are Lost," Neuroscience 24(1):161-174).
When systemically injected, MPTP easily diffuses across the blood-brain barrier and, due largely to the high concentrations of MOA-B in the walls of capillaries forming the blood-brain barrier, it is quickly converted to MPP+and does not rediffuse back across into systemic circulation. On the other hand, a systemic injection of MPP+ is prevented from crossing the blood-brain barrier to exert neurotoxic effects due to the presence of the inherent quaternary pyridinium ion. (Miyake, H. and Chiueh, C. C. [1989], "Effects of MPP+ on the release of serotonin and 5-hydroxyindoleacetic acid from rat striatum in vivo," Eur. J. Pharmacology 166:49-55; Przedborski, S. et al. [1996], "Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity," Proc. Natl. Acad. Sci. 93(10):4565-4571.) Systemic administration of MPTP causes transient decreases in ATP levels in the liver and noradrenaline cells in the heart and adrenal gland. Even so, these cell types do not possess mechanisms to maintain MPP.sup.+ at high enough concentrations to cause sustained mitochondrial inhibition.
A cDNA protein transporter mechanism has been isolated and found to provide resistance to MPP+ toxicity. The RNA expression of this protective protein mechanism has been isolated in both the adrenal gland and monoaminergic cells of the brainstem. Also, the uptake of MPP.sup.+ by adrenal medullary chromaffin granules protects the mitochondria in these areas from exposure to the MPP.sup.+ generated oxidative phosphorylation inhibitor. Inhibition of monoamine oxidase prevents MPTP toxicity, and the monoamine oxidase inhibitor deprenyl slows progression of idiopathic Parkinson's Disease. (Liu, Y. [1992], "A cDNA That Suppresses MPP+ Toxicity Encodes a Vesicular Amine Transporter," Cell 70:539-551.) 7-Nitroindazole (7-NI) also protects MPTP-injected mice against nigrostriatal dopaminergic pathway damage. (Przedborski, S. et al. [1996], "Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity," Proc. Natl. Acad. Sci. 93(10):4565-4571.)
MPTP has been found to cause generalized reduction in NADH:ubiquinone oxidoreductase in rat brain, increase in activity of cytochrome-c oxidase and changes in activities of monoamine oxidase-A and -B, (MAO-A and -B) similar to haloperidol, which is 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butano ne (Prince, J. A. et al. [1997], "Neuroleptic-Induced Mitochondrial Enzyme Alterations in the Rat Brain," J. Pharmacology and Exp. Therapeutics, 280:261-267.) Agents which block MAO-B activity prevent neurons from damage by MPTP and similar neurotoxins. (U.S. Pat. No. 5,508,311.) Deprenyl and its metabolite desmethylsegiline are such protective agents. (Mytilineau, C. et al. [1997], "L-(-)-Desmethylselegiline, a Metabolite of Selegine [L-(-)-Deprenyl], Protects Mesencephalic Dopamine Neurons from Excitotoxicity in Vitro," J. Neurochemistry 68(1):434-436.)
Gonadotrophic hormones, especially estrogen, have been shown to function as neural protective chemicals for dopamine neurons. They not only protect dopamine neurons from MPTP toxicity, but increase dopamine release and upregulate receptor transcripts. (Dluzen, D. E. et al. [1996], "Estrogen Alters MPTP-Induced Neurotoxicity in Female Mice: Effects on Striatal Dopamine Concentrations and Release," J. Neurochem. 66(2):658-666.)
Neural protective agents for other types of neurons include desipramine, which blocks the reuptake of norepinephrine (NE) a thousand times more effectively in the cortical areas than the corpus striatum, making it superior to mazidol which also provides some protective blocking, and citalopram, which prevents serotonin reuptake and also preserves the serotonin or indolamine neurons exposed to MPP+ from degeneration. (Javitch, J. A. et al. [1985], supra.) L-Dopa augments dopamine following MPTP administration. (Yang et al. [1986], "Depletion of glutathione in brainstem of mice caused by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is prevented by antioxidant pretreatment," Neuroscience Letters 63:56-60.) Guanethidine, a sympatholytic agent, 10 mg/kg, given s.c. once daily three days prior to systemic MPTP injections in rats, prevents peripheral catecholamine release by MPTP and/or MPP.sup.+ without interrupting desired effects of dopamine cell attenuation. (Giovanni, A. et al. [1994a], "Studies on species sensitivity to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Part 1: Systemic administration," J. Pharmacology and Exp. Therapeutics 270:1000-1007).
There are marked species differences in susceptibility to the neurotoxic effects of MPTP. Humans, non-human primates and mice are sensitive to MPTP, whereas rats are relatively insensitive to its effects. (Giovanni, A. et al. [1994], "Studies on Species Sensitivity to the Dopaminergic Neurotoxin 1-Methyl-4-Phenyl-1,2,3,6-Tetrayhydropyridine. Part 2. Central Administration of 1-Methyl-4-Phenylpyridinium," J. Pharmacology and Exp. Therapeutics 270:1008-1014.) Certain strains of mice (i.e. the Black C57 or C57B1) appear susceptible to MPP+, whereas other species of mice and rats are not. Age is also a factor in MPTP-induced dopamine cell loss, with older animals appearing more sensitive to neural toxicity. Parkinson's disease also generally has a relatively late onset. In a study undertaken with rhesus monkeys, motor effects were first observed after dosages of 0.66 mg/kg, while lesser dosages, e.g. about 0.275 to 0.44 mg/kg, markedly decreased dopamine levels. (Burns, R. S. et al. [1983], "A primate model of parkinsonism: Selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine," Proc. Nat'l Acad. Sci. 80:4546-4550.) In marmosets, behavioral changes and biochemical recovery were observed several months after administration of 1-4 mg/kg of MPTP. (Waters, C. M. et al. [1987], "An Immunohistochemical Study of the Acute and Long-term Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the Marmoset," Neuroscience 23(3):1025-1039.) Humans are five to ten times more sensitive to the neurotoxic effects of MPTM than primates. (Ricuarte, G. A. et al. [1988], "(+/-) 3,4-Methylenedioxymethamphetamine Selectively Damages Central Serotonergic Neurons in Nonhuman Primates," J. Am. Med. Assn. 260:51-55.)
A number of analogs of MTPT and MPP.sup.+ have been shown to have neurotoxic effects similar to MPTP. (Youngster, S. K. et al. [1989], "Oxidation of Analogs of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine by Monoamine Oxidases A and B and the Inhibition of Monoamine Oxidases by the Oxidation Products," J. Neurochemistry 53(6):1837-1842; Maret, G. et al. [1990], "The MPTP Story: MAO Activates Tetrahydropyridine Derivatives to Toxins Causing Parkinsonism," Drug Metabolism Reviews 22(4):291-332; Rollema, H. et al. [1990], "In Vivo Intracerebral Microdialysis Studies in Rats of MPP+ Analogues and Related Charged Species," J. Med. Chem. 33:2221-2230; Naiman, N. et al. [1990], "Studies on 4-Benzyl-1methyl-1,2,3,6-tetrahydropyridine, a Nonneurotoxic Analogue of the Parkinsonian Inducing Agent 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine," Chem. Res. Toxicol. 3:133-138; Dalvie, D. et al. [1992], "Characterization of an Unexpected Product from a Monoamine Oxidase B Generated 2,3-Dihydropyridinium Species," J. Org. Chem. 57:7321-7324; Tipton, K. F. and Singer, T. P., "Advances in Our Understanding of the Mechanisms of the Neurotoxicity of MPTP and Related Compounds," Journal of Neurochemistry 61(4):1191-1206; Castagnoli, Jr., N. and Castagnoli, K. P. [1998] NIH web page http://www.nida.nih.gov.)
Pyridine compounds which have been suggested for use as antipsychotics include C-1007, (R)(+)-1,2,3,6-tetrahydro-4-phenyl-1[(3-phenylcyclohexen-1-yl)methyl]pyrid ine (Wright, J. L. et al. [1995], "Identification, characterization and pharmacological profile of three metabolites of (CI1007), a dopamine autoreceptor agonist and potential antipsychotic agent," J. Med. Chem. 38:507-5014; Pugsley, T. A. et al. [1995], "I-1007, a Dopamine Partial Agonist and Potential Antipsychotic Agent. I Neurochemical Effects," J. Pharmacology and Exp. Therapeutics 274:898-911; Feng, M. R. et al. [1997], "Determination of two CI-1007 sulfate metabolites in monkey plasma and urine," J. Chromatogr. B 693:159-166; Meltzer, L. T. et al. [1995], "CI-1007, a Dopamine Partial Agonist and Potential Antipsychotic Agent. II Neurophysiological and Behavioral Effects," J. Pharmacology and Exp. Therapeutics 274:912-920; Feng, M. R. et al. [1997], "Pharmacokinetics and Pharmacodynamics of an Investigational Antipsychotic Agent, CI-1007, in Rats and Monkeys," Pharmaceutical Res. 14(3):329-336; Sramek, J. J. et al. [1998], "Initial Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of CI-1007 in Patients with Schizophrenia," Psychopharmacology Bull. 34(1):93-99). CI-1007 is not described as a neurotoxin.
U.S. Pat. No. 5,585,388 issued Dec. 17, 1996 to Cosford et al. for "Substituted Pyridines Useful as Modulators of Acetylcholine Receptors" discloses a number of pyridine-based compounds useful as modulators of acetylcholine receptors and said to be useful in the treatment of a wide range of disorders including tardive dyskinesias. No neurotoxic effects of these compounds are disclosed or suggested.
A method for treating schizophrenia which does not cause the serious side effects of neuroleptic drugs is needed. Such a treatment should be permanent, i.e. irreversible, or long-term.